Tumor metastasis is the dominant cause of death in cancer patients, including oral squamous cell carcinoma (OSCC) patients. However, the molecular and cellular mechanisms underlying tumor metastasis are still elusive. The identification of molecular markers associated with the metastatic process would help understand biological mechanisms and facilitate the development of therapeutic interventions for OSCC patients. This proposal aims to test the hypothesis that serum proteomic markers can be used to stratify metastatic from non-metastatic oral cancers. Two specific Aims are in place to test the hypothesis. Aim 1 is to engage a quantitative proteomics platform, iTRAQ and 2-D LC-MS/MS, to harness serum signature proteins associated with lymph node metastasis of tongue SCC. Aim 2 is to conduct AQUA validation of the candidate markers discovered in Aim 1 and build multi-marker prediction models for lymph node metastasis of tongue SCC. The overarching goal of the proposal is to discover serum proteomic markers and then translate the proteomic discoveries into prediction models that can forecast lymph node metastatic potential of primary tongue cancer, and thus improve clinical treatment decisions in the management of oral tongue cancer. This proposal will discover serum protein biomarkers for fast screening and assessment of lymph node metastasis of tongue cancer and improve clinical treatment of oral tongue cancer patients.